The Cardio-Renal
Advisory Committee is asked to opine on the relative efficacy of
an antihypertensive regimen containing
candesartan compared with a regimen containing
losartan at a dose of 100 mg per day.
Specific guidance is sought on the adequacy of the
current program to support a claim of superior efficacy for candesartan when
compared with losartan, as well as guidance on how to describe any
relevant differences in labelling. Specific
guidance is also sought on the adequacy of the
advice we have given sponsors, intended to
guide future development programs. whether an observed mortality difference can be a
compelling finding far out of proportion to its place in a study's formal hypothesis
testing.

In the past, the Agency
has told sponsors that demonstrating superiority to another antihypertensive
medication on blood pressure lowering was a
relevant clinical benefit, and that such a claim required the following data:

1)Evaluation of the
antihypertensive effects of the respective drugs at the highest approved doses.
If the
comparison was not done with the approved product, bioequivalence of the study
formulation and the approved product must be demonstrated. If the
comparison is not done with the approved product, bioequivalence of the study
formulation and the approved product must be demonstrated. Our
recommendation has been that this evaluation should include at least two
forced-titration trials to adequately assess the drug’s relative
antihypertensive effects. We have also said that unless a placebo group is
included in the trials no information about absolute antihypertensive efficacy
can be inferred; only comparative
antihypertensive effect.

2)Data comparing the
safety of the two agents, providing evidence that they do
not significantly differ with regard to adverse effects not captured by changes
in blood pressure.

The present sponsor has
provided data from three randomized trials, including two forced-titration
trials. These were conducted comparing candesartan force-titrated to a dose of
32 mg per day and losartan force-titrated to a dose of 100 mg per day. The
Agency and the sponsor have agreement with
regard to the numerical results of the efficacy analyses for
the three trials.OverallAt the
end of 8 weeks, candesartan 32 mg reduced
diastolic BP by around 3 mmHg more at trough than did losartan 100 mg when given once per day.Carvedilol is indicated for the reduction of mortality and the reduction of
hospitalization in patients with mild to moderate heart failure.With the results of the CAPRICORN
study, the sponsor seeks to extend the indication for carvedilol to patients
with left ventricular dysfunction subsequent to myocardial infarction.

In CAPRICORN, 1959 subjects with left ventricular ejection fraction <40%
and no heart failure, within 21 daysof myocardial infarction, were randomized to placebo or to carvedilol 6.25 mg bid, titrated as
tolerated to 25 mg bid over several weeks, and then followed for a mean of 15 months. The primary end point was
overall mortality, but, as a result of a protocol amendment late in the study,
there were two primary end points, time to cardiovascular hospitalization or death from any cause(assigned alpha of 0.045)
and time to
death alone
(assigned alpha of 0.005). After a single interim analysis, conducted after
the change in end point, the final results were as follows:

Events

Hazard

ratio

(95% CI)

P value

Alpha

Placebo

N=984

Carvedilol

N=975

Death or CV
hospitalization

367

340

0.92

(0.80-1.07)

0.297

0.045

Death

151

116

0.77

(0.60-0.98)

0.031

0.004

1.Regarding
the candesartan development program:

1.1.The
sponsor compared once per day dosing for both products, although the labeling
for both includes the possibility that twice per day dosing may be more
effective.

1.1.1.Did the
program compare the highest labeled dose of candesartan with the highest
labeled dose of losartan?

1.1.There
was no significant change in mean BP when patients were titrated from 16 to 32
mg of candesartan and from 50 to 100 mg of losartan.

1.1.1.How do
you explain this?

1.1.1.Is this
observation relevant for the relative efficacy of these two products?

1.

There was no significant
change in blood pressure when patients in either treatment group were titrated from the starting dose to
the target dose.

1.1.How do you explain this?

1.1.Is this observation
relevant to the superiority claim?
<What are you expecting the Cmte to say?>

Regarding
relative antihypertensive efficacy, compare the benefits of being ‘superior’ in
lowering BP compared with another approved antihypertensive drug to lowering BP
compared with placebo:

1.1.1.More
beneficial than lowering BP to an equal degree with compared with placebo.

1.1.1.Equal
to being superior in lowering BP to an equal degree when compared with placebo.

1.1.1.Less
beneficial than lowering BP to an equal degree when compared with placebo.

1.1.1.Overall,
candesartan reduced diastolic BP by around 3 mm Hg at the trough measurement
relative to losaratan in the two forced-titration studies. Are these
differences in BP lowering reported in these trials for candesartan and
losartan clinically meaningful?

1.

1.Studies are designed to test a formal hypothesis.
We usually, but arbitrarily, say a study is "successful" if the null
hypothesis is rejected at p<0.05, meaning that, on average and without
considering other internal data from this study or data from other studies, no more than once in 20
times (or once
in 40 times for a favorable
result) will we be misled into believing a result
that is not reproducible. Furthermore, to consider a finding to be compelling, we usually expect evidence equivalent to more than one study
successful at p=0.05. Let us define "discovery" as any opportunity to declare
a finding to be compelling outside of formal hypothesis testing. Discovery comes at the cost of increasing the false positive rate.

1.1.How much are you willing to inflate the false
positive rate in order to enable discovery? The response for each question need not be mutually exclusive.

1.2.For every potential discovery one can make in a
study, the risk of a false positive result increases. How many opportunities
should a study have for discovery?

1.3.When should a discovery be confirmed in a separate
formal hypothesis test?

1.4.Do you believe it is always possible to discover
something about mortality; i.e., is mortality always a primary end point? If so,
of what value
is making it a
formally tested hypothesis?

2.Without formally
specifying how we do so, we may be comforted or discomforted about a finding by other information
derived from the study. In considering the mortality effect discovery in
CAPRICORN, how do the following affect your confidence?

2.1.The effect on cardiovascular hospitalization.

2.2.Consistency of the mortality effect across
prespecified subgroups.

2.3.Consistency of the mortality effect across non-prespecified
subgroups.

2.4.[e.g
diuretics, beta blockers]Other secondary end points suggestive of a
mechanism for the mortality effect.

3.Without formally
specifying how we do so, we may be comforted or discomforted about a finding by information derived
from other studies.In considering the
mortality effect discovery in CAPRICORN, how do the following affect your
confidence?

In
other populations (e.g., (e.g., post-MImyocardial
infarction such as CYP2D6 or CYP 3A4 inhibiton

4.Without formally
specifying how we do so, we may be comforted or discomforted about a finding by information derived
from studies of related drugs.

1.1.wethe
DivisionCan
the estimate of effect versus placebo be made? , an amount that would be
sufficient for approval when compared with placebo for a comparison between two
antihypertensivesWhat comparative safety
data would be necessaryAre the comparative safety data submitted by the
sponsor sufficient

1.1.Would your answer be
different if the two drugs were from different drug classes (e.g., calcium-channel blocker and diuretic)?

The sponsor has
summarized the available safety data from the submitted trials in your briefing
book. Consider the importance of relative safety in assessing superiority
claims for antihypertensives with extensive post-marketing safety databases.

1.1.Are the submitted data
adequate to compare the safety of losartan and candesartan?

1.1.1.If not, what additional
information is needed?

1.1.1.1.Would your answer change
if the comparator was from a different drug class (e.g.,
calcium-channel blocker)?

1.1.1.If so, are there safety
concerns that undermine or enhance the relative risk/benefit ratio for
candesartan when compared with losartan?

1.Do you recommend approval
of candesartan as having demonstrated
superior antihypertensive efficacy when compared with losartan?

4.1.If one were to do that with post-MI use of carvedilol, would one
include any drug with any of its pharmacological properties¾beta blocker, alpha
blocker, free radical scavenger, anti-hypertensive¾or only drugs with all of
these properties?

4.2.Would one be interested in survival trials only, any trials with
survival data, or
other end points
as well?

1.1.Are there relevant
results with other drugs

4.3.Of combination products containing candestartan or
losartan?

5.All things considered, how likely is it that the mortality effect in CAPRICORN represents an effect attributable
to carvedilol?

6.Should carvedilol be
indicated to reduce mortality in patients with left ventricular dysfunction
after myocardial infarction?

7.The Sponsor also seeks a claim for reduction in
recurrent MI, based on the observation of 45 adjudicated events on placebo and
27 on carvedilol (of which 16 and 12 were fatal). Do these data support a
claim?

If so,
how should the findings of these trials be included in the approved labeling:

1.1.1.For Candesartan?

1.1.1.1.How
should the potential use of losartan 50 mg BID be reflected in the label?